Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

eLife

Humberto C Joca¹  Ricardo A Feldman²  Manasa P Srikanth²  Jenna M Leser³  Olivia M Torre³  Christopher W Ward³  Katrina M Williams³  Joseph P Stains³  James S Lyons³  Marcus Hughes³  Nicole R Gould³  Ramzi J Khairallah⁴ 

[1] Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States;Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, United States;Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States;Myologica, LLC, New Market, United States;

关键词: osteocyte;    sclerostin;    parathyroid hormone;    lysosome;    mechanical load;    bone;    Mouse;   

DOI  :  10.7554/eLife.64393

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minute-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically and hormonally activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.

【 授权许可】

CC BY